Tenofovir (TNV) and emtricitabine (FTC) are generally safe, effective, and exhibit appealing pharmacokinetic properties, as the pharmacologically-active phosphorylated moieties exhibit a long half-life in mononuclear cells of HIV-infected patients. These favorable characteristics provide an impetus to evaluate TNV and FTC in a new clinical setting, pre-exposure HIV prophylaxis in HIVnegative persons (PreP). Several large phase-III clinical trials for PreP are currently underway. However, no studies have compared the cellular pharmacology of TNV/FTC in HIV-negative versus HIV-infected persons. Without this knowledge, it is impossible to make the most informed dose and dosing decisions for this new indication. This application proposes a planning period in preparation for a phase II clinical research study to define and compare the cellular pharmacology of TNV and FTC in HIV-seronegative versus HIV-seropositive adults. The two goals of the planning period are: To fully develop a comprehensive manual of operations for the conduct of the phase II study and to submit complete documentation to all necessary regulatory agencies. The overall hypothesis for clinical [unreadable] research study is that HIV-infection significantly influences the cellular pharmacology of TNV and [unreadable] FTC. To illustrate, intracellular TNV-phosphates, the focus of our studies, are 3-fold higher and persist [unreadable] for 3-fold longer in resting versus activated mononuclear cells in vitro. We propose that these in vitro [unreadable] findings are relevant to humans because HIV infection significantly elevates the activation-state of [unreadable] mononuclear cells and tissues in vivo. Our study will elucidate, according to HIV serostatus, the rate [unreadable] that intracellular TNV/FTC rise to steady-state (relevant for the onset of action) and the terminal [unreadable] elimination rate (relevant for missed doses, dosing interruptions, and potential window for resistance). [unreadable] We will also investigate the potential for TNV to inhibit purine nucleoside phosphorylase (PNP) in vivo. [unreadable] The rationale for this aim arises from an in vitro study which showed that TNV-monophosphate [unreadable] potently inhibited PNP-mediated didanosine (ddI) breakdown. It is not known, however, whether TNV [unreadable] causes a generalized PNP inhibition in vivo, which is a fundamental gap in basic knowledge. Indirect [unreadable] evidence makes a case that TNV does in fact cause a generalized PNP inhibition in vivo, as TNV is [unreadable] associated with unexpected T-lymphocytopenia and, in other studies, hypouricemia. Our study will [unreadable] quantify, for the first time, generalized PNP inhibition by TNV in vivo. If our overall hypothesis is [unreadable] correct, TNV-phosphates will be higher in the "resting cell-state" of HIV negative persons and [unreadable] generalized PNP inhibition will be more pronounced in these persons compared with HIV-infected [unreadable] persons. The new information learned in this phase II study will directly address the most important [unreadable] and clinically relevant pharmacologic considerations applicable to the indication of PreP. [unreadable] [unreadable] [unreadable] [unreadable]